New Jersey Under Fire for Selective Scrutiny of Fentanyl Sublingual Spray

When the state of New Jersey decided to target physicians prescribing fentanyl sublingual spray (Subsys, INSYS Therapeutics) in an off-label manner, it not only made headlines but opened up an ethical debate that spanned medical specialties and state boundaries: Should drugs be used for off-label purposes? And what role should state agencies play in the regulation of such prescriptions, particularly when—as in the case of these transmucosal immediate-release fentanyl (TIRF) formulations—they choose to target only one of several drugs in a class?

Clinical Benefits and Inherent Dangers

The potential adverse health consequences of prescription opioid analgesics are well documented and include abuse, addiction and death due to overdose. The TIRF products, which are FDA approved for use in cancer patients with breakthrough pain, are part of an FDA Risk Evaluation and Mitigation Strategy (REMS) program. The goals of the FDA-required TIRF REMS are to ensure patient access to these medications and to mitigate the risk for misuse, abuse, addiction, overdose and serious complications due to medication errors.

In the practice of pain management, clinicians are faced with treating refractory, challenging, noncancer pain syndromes in which flares or breakthrough episodes of pain are paroxysmal and come on suddenly. Although approved only for cancer pain, the TIRF rapid-onset opioids are often optimal for breakthrough pain in noncancer pain. There are currently six approved TIRF products, of which one has received the most scrutiny. All FDA-approved TIRF medications rapidly deliver the drug, albeit through different routes of administration. Subsys itself is a spray version of fentanyl, and typically administered under the user’s tongue.

In an October 2016 letter to the FDA, Sen. Edward Markey (D-Mass.) stated that INSYS aggressively and illegally pushed off-label prescribing of their TIRF fentanyl product (www.markey.senate.gov/?imo/?media/?doc/?2016-10-11-FDA-Fentanyl-letter.pdf).

On Oct. 17, 2016, New Jersey released a consumer alert warning the public about the “dangers” of using sublingual fentanyl spray outside its approved use. The alert was issued after the state filed an action seeking the temporary license suspension of a Cherry Hill, N.J., doctor who prescribed the drug to a noncancer patient; the patient later died from a suspected overdose. As noted in its press release of that date, the state maintained, “Prescribing Subsys for anything other than its approved use, a practice known as ‘off-label’ prescribing, carries an increased risk of misuse, abuse, addiction, overdose and death. The medicine is not for use in opioid non-tolerant patients because life-threatening respiratory depression and death could occur at any dose in patients not taking chronic opioids.’

No reasonable clinician would deny that a powerful, rapid-onset opioid has clear and dangerous risks: Overdose or misuse can readily result in patient death, which has already occurred in several instances across the country. This led New Jersey to take its apparently radical steps.

Yet the state’s actions went much farther than merely warning patients about the potential risks of the drug. The attorney general of New Jersey also instructed the New Jersey Division of Consumer Affairs to investigate what he called “the potential misuse of this highly addictive medication by other providers,” stating, “any physicians who prescribe Subsys for any other use are deviating from the regulatory standard of care deemed appropriate for this drug and are exposing their patients to a grave risk of a fatal overdose.”

Treating Chronic or Intractable Pain

But is that truly the case? According to Jeffrey Gudin, MD, director of pain management and palliative care at Englewood Hospital and Medical Center, in Englewood, the majority of patients who receive TIRF formulations are not cancer patients, and thereby are receiving the drug in an off-label manner. “I would estimate that about 80% of prescriptions for these fentanyl products are written for noncancer pain,” Dr. Gudin said in an interview. Most patients being treated with TIRF formulations, he said, are those with chronic pain or intractable breakthrough pain that is not being effectively treated by any other therapeutic agents. He added that TIRF products are often not used as first-line therapy.

“For example, a patient has trigeminal neuralgia and is hit with a lightning bolt of pain in the face that lasts only minutes,” he explained. “If he or she takes a pill, it takes 30 to 90 minutes for that pill to reach peak effect. There’s an illogical disconnect between the onset of pain and the therapeutic action of the medicine.

“Or let’s say you have a compression fracture,” Dr. Gudin continued. “So you get in the car or the bus or train, and you get rattled around a little. Now you’re in agony in a matter of a minute or two. You certainly don’t want to take a pill that takes 60 minutes to reach its peak.”

Certainly, the concern around misuse of TIRF products is valid. The drugs are extraordinarily potent, and potentially lethal when prescribed to opioid-naive individuals—a strict contraindication. This is undoubtedly why the FDA included the agents in their REMS program.

Currently, dozens of agents are the subject of REMS programs. The scope of the program is extremely comprehensive, providing educational information to health care providers who prescribe the agents, the patients taking them and the pharmacies that dispense them. Among other things, prescribing physicians are asked to enroll in the REMS program and complete an education program that includes a knowledge assessment. However, such lofty goals have not prevented some physicians from misprescribing the agents, sometimes with catastrophic and even deadly results.

Deaths associated with the inappropriate use of medications are always tragic, but do they warrant the actions taken by the state to target all physicians prescribing off-label fentanyl sublingual spray? To Dr. Gudin, the answer is a clear no, given the frequency with which other agents are used in an off-label manner.

“We need to recognize that the majority of these products are being used off-label and make sure that clinicians who are using them are appropriately educated,” he said. “But I don’t think we need to scrutinize the physician just because he or she chose this class or this particular medicine. If physicians think in their clinical judgment that a patient warrants a TIRF, then as long as they’re skilled in prescribing these medicines, they shouldn’t have to fear disciplinary action for writing an off-label drug.”

Off-Label Use Questioned

Off-label drug use is commonplace, entirely legal and widely accepted. Indeed, according to G. Caleb Alexander, MD, co-director of the Johns Hopkins University’s Center for Drug Safety and Effectiveness, in Baltimore, off-label use is so common that virtually every drug is used off-label at some point. Indeed, myriad studies are approved by both local institutional review boards and the FDA every year for off-label use of drugs.

Most agree that off-label prescribing plays an important role, both in drug development and when patients have exhausted other options. Medical societies such as the American Cancer Society recognize its utility, pointing out that cancer treatment often involves off-label drug use.

In pain medicine, there are many examples of drugs used commonly and successfully in off-label circumstances. “The antidepressant amitriptyline is one of the most common tricyclic antidepressants,” Dr. Gudin noted. “We use them off-label for neuropathic pain every single day.

“The lidocaine patch is approved only for postherpetic neuralgia,” he continued. “Nevertheless, I’d say the majority is used for low back and musculoskeletal pain.” Other examples include beta blockers, which are FDA approved for treating high blood pressure but widely recognized as standard of care for patients with heart failure, and antipsychotics, which are often used for attention-deficit hyperactivity disorder.

Yet all is not so rosy when it comes to off-label use. Take the example of the drug cocktail fen-phen. The FDA approved fenfluramine hydrochloride and phentermine hydrochloride as individual, short-term treatments for obesity. When an article describing the beneficial effects of combining the two appeared (Clin Pharmacol Ther 1992; 51:642-646), doctors began to prescribe the two drugs together—sometimes with devastating results. Some patients ended up with severe heart valve damage, which ultimately triggered a multibillion-dollar lawsuit. The FDA ordered fen-phen off the market in 1997.

A Clinician’s Skilled Hands

When it comes to TIRF formulations, Dr. Gudin noted that given the inherent potency and related danger of the agents, they should only be prescribed by doctors skilled in their use. “The last thing I want is for physicians to think they should be prescribing more of this class of drug,” he commented. “This is a clinically useful, yet very sensitive, class of medication that is associated with serious risks, and should only be used appropriately by clinicians skilled in prescribing it.” Among other things, patients receiving TIRF formulations need to be opioid tolerant.

Why fentanyl sublingual spray has been specifically targeted in New Jersey while other TIRF formulations have apparently been ignored has left some physicians scratching their heads, although it’s possibly a byproduct of the allegations into executives at INSYS. In December 2016, the former CEO and several other top-level managers of the company were arrested on federal charges of conspiring to bribe doctors to prescribe the drug. In a 60-page indictment, the defendants were charged with “devising and fostering a scheme to bribe practitioners” to write large prescriptions of the drug as well as conspiring to mislead insurers when it came to reimbursement.

“The long and the short of it is this,” Dr. Gudin explained. “If there’s evidence that a certain class of drug is dangerous to the public, then it is sensible to issue a warning about the entire class, not just one. But just to jump on the political bandwagon because INSYS is under investigation by the government and scrutinize physicians who write that specific product seems a bit unfair.”

Meanwhile, New Jersey continues its efforts unabated. In January, its board of medical examiners temporarily suspended the license of a physician who allegedly prescribed the agent off-label. The pain management specialist became the third New Jersey physician suspended for prescribing the agent to noncancer patients. The attorney general was adamant about the state’s ongoing efforts. “We will do everything within our regulatory power to stop irresponsible physicians from exposing patients to grave danger or death by indiscriminately prescribing them these highly-restricted drugs,” he said in a press release.

Do cases like this mean the entire class of drugs is damned? Dr. Gudin says tarring responsible physicians for the actions of a few irresponsible ones is misguided. “Certainly there are physicians who have used TIRFs inappropriately, and we can learn from those,” he said, adding they should be penalized or remediated. “There is utility in this class of product, but it needs to be treated with respect because they can cause respiratory depression like any other opioid, especially in those who are opioid naive.”

In the end, the off-label use of any drug, including TIRF formulations, is far from black and white. Its demonstrated benefits are myriad, but the specter of adverse events looms. As Sandeep Gupta, MBBS, MD, stated in his 2014 article (J Pharmacol Pharmacother 2014;5:88-92), “Off-label use might be compared to a double-edged sword which might be very useful for some patients while it can also expose them to unrestricted experimentation, unknown health risks, or ineffective medicine.

“Hence, there is an urgent need for guidance to encourage proper off-label use of medicine by the distribution of scientifically valid and authentic information from the pharmaceutical companies.”

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